Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus

被引:141
作者
Guo, Christine
Martinez-Vasquez, Diego
Mendez, Gonzalo P.
Toniolo, Maria F.
Yao, Tham M.
Oestreicher, Eveline M.
Kikuchi, Taisuke
Lapointe, Nathalie
Pojoga, Luminita
Williams, Gordon H.
Ricchiuti, Vincent
Adler, Gail K.
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens,Dept Med, Boston, MA 02115 USA
[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA
关键词
D O I
10.1210/en.2006-0944
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin-(55 mg/kg) treated rats (n = 11), diabetic streptozotocin- treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGF beta mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.
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页码:5363 / 5373
页数:11
相关论文
共 53 条
[1]  
Abbate M, 1998, J AM SOC NEPHROL, V9, P1213
[2]   Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction [J].
Al Suwaidi, J ;
Hamasaki, S ;
Higano, ST ;
Nishimura, RA ;
Holmes, DR ;
Lerman, A .
CIRCULATION, 2000, 101 (09) :948-954
[3]   SHORT AND LONG-TERM EFFECTS OF ANTIHYPERTENSIVE THERAPY IN THE DIABETIC RAT [J].
ANDERSON, S ;
RENNKE, HG ;
GARCIA, DL ;
BRENNER, BM .
KIDNEY INTERNATIONAL, 1989, 36 (04) :526-536
[4]   MEAN GLOMERULAR VOLUME AND RATE OF DEVELOPMENT OF DIABETIC NEPHROPATHY [J].
BILOUS, RW ;
MAUER, SM ;
SUTHERLAND, DER ;
STEFFES, MW .
DIABETES, 1989, 38 (09) :1142-1147
[5]   Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy [J].
Brenner, BM ;
Cooper, ME ;
de Zeeuw, D ;
Keane, WF ;
Mitch, WE ;
Parving, HH ;
Remuzzi, G ;
Snapinn, SM ;
Zhang, ZX ;
Shahinfar, S .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 345 (12) :861-869
[6]  
Breyer MD, 2005, J AM SOC NEPHROL, V16, P27, DOI [10.1681/ASN.2004080648, 10.1681/ASN.2009070721]
[7]   Role of aldosterone in diabetic nephropathy [J].
Cha, DR ;
Kang, YS ;
Han, SY ;
Jee, YH ;
Han, KH ;
Kim, HK ;
Han, JY ;
Kim, YS .
NEPHROLOGY, 2005, 10 :S37-S39
[8]   Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data [J].
Chaturvedi, N .
ANNALS OF INTERNAL MEDICINE, 2001, 134 (05) :370-379
[9]   Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis [J].
Chow, FY ;
Nikolic-Paterson, DJ ;
Atkins, RC ;
Tesch, GH .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2004, 19 (12) :2987-2996
[10]  
Cohen MP, 1996, EXP NEPHROL, V4, P166